Researchers at Cambridge and UCL reported on Wednesday that in 47 UK women who later developed acute myeloid leukaemia, the first cancer-driving mutation was often acquired before age 20.
In two-thirds of cases that first mutation arose more than 50 years before diagnosis, according to the paper in Nature. The women were diagnosed with the disease (AML) at an average age of 72.
The team used stored blood samples from the University of Cambridge study’s source trial, the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), in which around 50,000 women gave a blood sample every year for up to 11 years.
Some samples dated back 15 years before diagnosis.
They compared the 47 women with matched samples from 46 women who stayed free of blood cancer, using ultra-sensitive DNA sequencing and mathematical modelling to estimate when each mutation arose and how fast the affected cells multiplied.
The first mutation was followed by decades of slow growth, with cells taking years to double in number. Each further mutation raised the growth rate around two- to three-fold, and cells carrying four cancer-driving mutations doubled in a matter of weeks.
Professor Jamie Blundell, from the Early Cancer Institute at Cambridge, who led the work, described the stored samples as a “fossil record” of the blood’s evolution that lets researchers reconstruct when each mutation arose.
In at least a third of the AML cases, one clone of mutated cells had come to dominate the blood years before diagnosis, a pattern called a somatic sweep. None was seen in the cancer-free women.
The team checked the link with UK Biobank data, which showed people with such sweeps were at greatly increased risk of AML.
In around one in five cases, the expanding mutated cells were not detectable until one to two years before diagnosis, so the warning period may be shorter for some people.
AML affects around 2,700 people in the UK each year, and only around one in six survive five years after diagnosis. Many healthy older people carry blood cells with leukaemia-linked mutations, but only a small proportion go on to develop the disease.
Study rests on 47 cases and no samples from diagnosis
The work is observational and rests on 47 cases. The women were diagnosed between the ages of 53 and 83, and the samples were not taken at the time of diagnosis.
The Nature paper notes that the investigators were not blinded to which women had developed AML during sequencing and analysis.
Preventive treatment has not been tested.
The team’s modelling suggests that even a small cut in a clone’s growth rate over the decade or more before diagnosis could substantially reduce the risk of progression.
Testing whether that can be done safely and effectively in people at high risk is the team’s next step.
Dr Caroline Watson, the first author, sees patients at the Cambridge Clonal Haematopoiesis Clinic at Addenbrooke’s Hospital, which monitors people who carry such mutations. She said the findings “point to a window in which prevention could one day be possible”.
Samples from a 2001 trial in which screening did not cut deaths
UKCTOCS was designed to test ovarian cancer screening, not leukaemia. It enrolled women aged 50 to 74 between 2001 and 2005, and in 2021 UCL reported that neither screening approach reduced deaths compared with no screening.
The stored samples were a by-product of that trial. Professor Usha Menon of UCL, who led UKCTOCS, said a key outcome was “a unique bioresource of serial serum samples”.
The MRC Clinical Trials Unit at UCL has said the resource is already used by researchers worldwide, including to evaluate new early detection tests for other cancers and for cardiovascular disease.
The leukaemia research was largely funded by UK Research & Innovation and Cancer Research UK.